The Value of Interleukin-12 as an Activity Marker of Pulmonary Sarcoidosis

Kim, Tae Hyung; Jeon, Yong Gam; Shim, Tae Sun; Lim, Chae Man; Koh, Yunsuck; Lee, Sang Do; Kim, Woo Sung; Kim, Won Dong; Kim, Dong Soon

Abstract

BACKGROUND: Sarcoidosis is a chronic granulomatous inflammatory disease of unknown etiology often involving the lungs and intrathoracic lymph nodes. The natural course of sarcoidosis is variable from spontaneous remission to significant morbidity or death. But, the mechanisms causing the variable clinical outcomes or any single parameter to predict the prognosis was not known. In sarcoidosis, the number and the activity of CD4+ lymphocytes are significantly increased at the loci of disease and their oligoclonality suggests that the CD4+ lymphocytes hyperreactivity may be caused by persistent antigenic stimulus. Recently, it has been known that CD4+ lymphocytes can be subdivided into 2 distinct population(Th1 and Th2) defined by the spectrum of cytokines produced by these cells. Th1 cells promote cellular immunity associated with delayed type hypersensitivity reactions by generating IL-2 and IFN-gamma. Th2 cells play a role in allergic responses and immediate hypersensitivity reactions by secreting IL-4, IL-5, and IL-10. CD4+ lymphocytes in pulmonary sarcoidosis were reported to be mainly Th1 cells. IL-12 has been known to play an important role in differentiation of undifferentiated naive T cells to Th1 cells. And, Moller et al. observed increased IL-12 in BALF in patients with sarcoidosis. So it is possible that the elevated level of IL-12 is necessary for the continuous progression of the disease in active sarcoidosis. This study was performed to test the assumption that IL-12 can be a marker of active pulmonary sarcoidosis.
METHODS
: We measured the concentration of IL-12 in brochoalveolar lavage fluid(BALF) and in conditioned medium of alveolar macrophage(AM) using ELISA(enzyme-linked immunosorbent assay) method in 26 patients with pulmonary sarcoidosis (10 males, 16 females, mean age : 39.8 +/-2.1 years) and 11 normal control. Clinically, 14 patients had active sarcoidosis and 12 patients had inactive.
RESULTS
Total cells counts, percentage and number of lymhocytes, number of AM and CD4/CD8 lymphocyte ratio in BALF were significantly higher in patients with sarcoidosis than in control group. But none of these parameters could differentiate active sarcoidosis from inactive disease. The concentration of IL-12 in BALF was significantly increased in sarcoidosis patients (49.3+/-9.2 pg/ml) than in normal control (2.5+/-0.4 pg/ml) (p<0.001). Moreover it was significantly higher in patients with active sarcoidosis (70.3+/-14.8 pg/ml) than in inactive disease (24.8+/-3.1 pg/ml) (p=0.001). Also, the concentration of IL-12 in BALF showed significant correlation with the percentage of AM(p<0.001), percentage(p<0.001) and number of lymphocyte (p<0.001) in BALF, suggesting the close relationship between the level of IL-12 in BALF and the inflammatory cell infiltration in the lungs. Furthermore, we found a significant correlation between the level of IL-12 and the concentration of soluble ICAM-1: in serum (p<0.001) and BALF (p=0.001), and also between IL-12 level and ICAM-1 expression of AM (p<0.001). The AM from patients with pulmonary sarcoidosis secreted significantly larger amount of IL-12 (206.2+/- 61.9 pg/ml) than those of control (68.3+/-43.7 pg/ml) (p<0.008), but, there was no difference between inactive and active disease group.
CONCLUSION
Our data suggest that the BALF IL-12 level can be used as a marker of the activity of pulmonary sarcoidosis.